This invention relates to novel compounds which are inhibitors of protein tyrosine kinases such as the Janus kinases (JAK1, JAK2, JAK3 and TYK2) and in particular Janus kinase 1 (JAK1).
Protein tyrosine kinases are a family of enzymes catalyzing the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Phosphorylation of tyrosine residues on protein substrates leads to transduction of intracellular signals which regulate a wide variety of processes such as cell growth differentiation and activation, metabolism, hematopoiesis, host defense and immuno-regulation. As the elucidation of the molecular mechanisms in a number of inflammatory conditions and other disorders of the immune system (e.g. autoimmune diseases), highlighted the critical role of these intracellular signal pathways, modulation of the activity of protein tyrosine kinases appears to be an attractive route to the management of inflammatory diseases. A large number of protein tyrosine kinases have been identified which may be receptor protein tyrosine kinases, e.g. the insulin receptor, or non-receptor protein tyrosine kinases.
The protein tyrosine kinases JAK1, JAK2, JAK3 and TYK2 selectively associate with the cytoplasmic domains of various cytokine receptor chains and have essential roles in cytokine-dependent regulation of tissue homeostasis, initiation of innate immunity, shaping adaptive immune responses and inflammatory processes. They are critical in signal transduction in response to their activation via tyrosine phosphorylation by stimulation of cytokine receptors. (1) Schindler C. et al. JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem 2007; 282(28):20059; (2) O'Shea J. J. Targeting the Jak/STAT pathway for immunosuppression; Ann. Rheum. Dis. 2004; 63 Suppl 2:ii67; (3) Schindler C. Series introduction. JAK-STAT signaling in human disease; J. Clin. Invest. 2002; 109(9):1133); (4) O'Shea et. Al. Cell, Vol. 109, S121-S131, 2002; (5) Schwartz D. M. et al. Nat. Rev. Rheumatol., 2016; 12(1): 25-36; (6) O'Shea et al. New. Eng. J. Med. 2013; 368(2): 161-170.
While JAK1, JAK2 and TYK2 are ubiquitously expressed JAK3 is predominantly expressed in hematopoietic cells.
JAK1 plays a critical role in mediation of biological responses and JAK1 is widely expressed and associated with several major cytokine receptor families. It is involved in signaling by members of the IL-2 receptor γ subunit family (IL-2, IL-4, IL-7R, IL-9R, IL-15R and IL-21R), the IL-4 receptor family (IL-4R, IL-13R), the gp130 receptor family and class II cytokine receptors comprising of IL-10 receptor family and both type I and type II IFN receptor family.
JAK2 is implicated in signaling by several single chain receptors (including Epo-R, GHR, PRL-R), the IL-3 receptor family, the gp130 receptor family, the IL-12 receptor family (IL-12 and IL-23) and some Class II receptor cytokine family. Thus, JAK2 plays a critical role in transducing signals for Epo, IL-3, GM-CSF, IL-5 and IFNγ. JAK2 knockout mice exhibit an embryonic lethal phenotype.
JAK3 is involved in signal transduction by receptors that employ the common gamma chain of the type I cytokine receptor family also known as IL-2 receptor family (e.g. IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). XSCID patient populations have been identified with reduced levels of JAK3 protein or with genetic defects to the common gamma chain, suggesting that immune suppression should result from blocking signaling through the JAK3 pathway. Animal studies have suggested that JAK3 not only plays a critical role in B and T lymphocyte maturation, but that JAK3 is constitutively required to maintain T cell function. Modulation of immune activity through this novel mechanism can prove useful in the treatment of T cell proliferative disorders such as immune system diseases, in particular autoimmune diseases.
TYK2 is implicated in type I interferons, IL-6, IL-10, IL-12 and IL-23 signaling. A human patient with a TYK2 deficiency has been described and this patient had a primary immunodeficiency disorder characterized as a hyper-IgE-like syndrome with many opportunistic infections by virus, bacteria and fungi. Because IL-23 has been found to play an important role in many chronic inflammatory conditions, a TYK2 inhibitor could conceivably be very effective in treating diseased influenced by IL-23.
Anemia and neutropenia may be related to inhibition of EPO and GM-CSF respectively, since the biological effect by these two cytokines apparently depends exclusively on JAK2 activation. Similarly, IL-12 and IL-23 are involved in engaging innate and adaptive immune defense to viruses, bacteria, and fungi. Because these cytokines bind to receptors that recruit JAK2 and TYK2 in their signaling cascade it is conceivable that a selective JAK1 inhibitor will not affect their biological activity and thus have a safer profile compared to compounds which inhibit JAK1, JAK2, JAK3 and TYK2.
Activation of JAK lead to the activation of STAT molecules and thus to the elicitation of JAK/STAT signaling pathway, which is highly regulated by phosphorylation events. Activation of STAT molecules is considered a valid pharmaco-dynamic marker for JAK activity and the activity of specific JAK molecules can be assessed by the level of preferential recruited active STAT molecule.
In particular, the receptor of IL-4 expressed by immune cells is constituted by two different chains, the ligand high affinity and signal transducer IL-4Ra and common-γ chain, activating JAK1 and JAK3 respectively upon ligand binding, which leads to the recruitment and activation of STAT6. Similarly, the IL-6 receptor is a heterodimer receptor formed by the IL-6 high affinity receptor chain (IL-6Ra) and the signal transducer glycoprotein 130 (gp130) chain to which JAK1 preferentially associates. The gp130 chain activates JAK1 and STAT3 signaling pathway upon ligand binding. Therefore, to investigate the activity of JAK1, the level of active STAT6 or STAT3 can be assessed in immune cells after stimulation with either IL-4 or IL-6, respectively.
Furthermore, the receptor for erythropoietin (EPOR) is a homodimer receptor constituted by two identical receptor chains. Therefore, the EPOR chain is both high affinity ligand binding and signal transducer chain and activates only the associated JAK2 molecule upon ligand binding, leading to the recruitment and activation of STAT5. Receptor for GM-CSF is a heterodimer receptor constituted by the GM-CSF high affinity receptor chain (GM-CSFRα) and the signal transducer chain (GM-CSFRβ), to which JAK2 specifically associates. Upon ligand binding, association of α and β receptor chains results in the activation of JAK2 and STAT5 signaling pathway. Therefore, to investigate the activity of JAK2, the level of active STAT5 can be assessed in immune cells after stimulation with either GM-CSF or erythropoietin (EPO).
Inhibitors of the Janus kinases are expected to show utility in the treatment of inflammatory and non-infectious autoimmune diseases wherein these kinases are involved. Recently the pan-JAK inhibitors tofacitinib and ruxolitinib have been launched for the treatment of rheumatoid arthritis and myelofibrosis, respectively. JAK1 inhibitor PF-04965842 is presently in phase III clinical trials for the treatment of atopic dermatitis, JAK1 inhibitor baricitinib has been launched for the treatment of rheumatoid arthritis and is in phase III trials for the treatment of atopic dermatitis and JAK1 inhibitor upadacitinib is presently in phase III clinical trials for the treatment of rheumatoid arthritis and psoriatic arthritis and in phase II trials for the treatment of atopic dermatitis, Crohn's disease and ulcerative colitis.
Hence, JAK inhibitors may furthermore be useful in the treatment of diseases related to activity of Janus kinases, including, for example skin diseases like psoriasis, atopic dermatitis, scleroderma, rosacea, skin cancers, dermatitis, dermatitis herpetiformis, dermatomyositis, vitiligo, alopecia areata, contact dermatitis, eczema, xerosis, ichthyosis, urticaria, chronic idiophatic pruritus, pyoderma gangrenosum, cutaneous lupus erythematosus and lichen planus; respiratory diseases like asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, rhinitis, bronchiolitis, byssinosis, pneumoconiosis, bronchiectasis, hypersensitivity pneumonitis, lung cancers, mesothelioma and sarcoidosis; gastrointestinal diseases like inflammatory bowel disease, ulcerative colitis, Crohn's disease, retroperitoneal fibrosis, celiac disease and cancers; eye diseases like myasthenia gravis, Sjögren's syndrome, conjunctivitis, scleritis, uveitis, dry eye syndrome, keratitis, iritis; systemic indications like lupus, multiple sclerosis, rheumatoid arthritis, type I diabetes and complications from diabetes, cancers, ankylosing spondylitis and psoriatic arthritis; cancer like bone and soft tissue tumors, head-neck cancer as well as other autoimmune diseases and indications where immunosuppression would be desirable for example in organ transplantation.
WO2013007768 discloses Tricyclic Heterocyclic Compounds, Compositions and Methods of use thereof as JAK Inhibitors.
WO2013007765 discloses Fused Tricyclic Compounds for use as Inhibitors of Janus Kinases.
WO2011086053 discloses Tricyclic Heterocyclic Compounds, Compositions and Methods of use thereof.
Zak, M. et. Al, J. Med. Chem., (2013), 56, 4764-85, discloses imidazopyrrolopyridines as JAK1 inhibitors.
There remains a need for new compounds which effectively and selectively inhibit specific JAK enzymes, in particular inhibitors which selectively inhibit JAK1 vs. JAK2 to reduce adverse effects without affecting the overall anti-inflammatory efficacy.